1. Field of the Invention
The present invention relates to the field of devices and methods for chemical synthesis, analysis, and biological screening. More particularly, the present invention relates to a new and improved apparatus for high-throughput combinatorial synthesis of organic molecules, particularly nucleic acids.
2. Description of Related Art
Solid-phase synthesis of organic molecules is the method of choice for preparation of libraries and compound megaarrays, which are currently being applied for screening in the quest to find new drugs or pharmaceutical lead compounds, i.e., compounds which exhibit a particular biological activity of pharmaceutical interest. These leads can serve as a starting point for the selection and synthesis of a drug compound, which in addition to the particular biological activity of interest has pharmacologic and toxicologic properties suitable for administration to animals, including humans.
Several designs of instruments for combinatorial synthesis utilizing solid-phase synthesis are known. An exemplar of the prior art is U.S. Pat. Nos. 5,202,418 and 5,338,831, to Lebl et al., which each describe a method of performing multiple synthesis of peptides on a solid carrier. U.S. Pat. No. 5,342,585 to Lebl et al. describes an apparatus for multiple syntheses of peptides on solid support. U.S. Pat. No. 6,045,755 to Lebl, et al. describes an apparatus and a method for combinatorial chemistry synthesis. U.S. Pat. No. 6,121,054 to Lebl, corresponding to PCT International Publication No. WO00/25470, shows a method for separation of liquid and solid-phases for solid-phase organic synthesis. The entire contents of the above patents are incorporated herein by this reference.
Liquid removal by centrifugation was described and is the subject of several publications. See Christian Birr, Aspects of the Merrified Peptide Synthesis (Springer-Verlag, New York 1978; German Patent Application P 20 17351.7, G. 70 13256.8, 1970. These references describe the use of centrifugation for liquid removal from slurry of solid-phase particles in a concentric vessel equipped with a filtration material in its perimeter and spun around its axis.
In summary, one aspect of the present invention is directed to an apparatus for performing combinatorial-chemistry synthetic reactions including a reaction vessel for containing a combinatorial-chemistry synthetic reaction, a liquid dispenser for dispensing the liquid, and a liquid aspirator and an adjustment mechanism. The reaction vessel includes an ingress aperture allowing a liquid to enter into an interior of the vessel and an egress aperture for aspirating the liquid from the vessel. The liquid dispenser dispenses liquid through the ingress aperture. The liquid aspirator aspirates liquid through the egress aperture and includes a rotor for carrying the vessel and orbiting the vessel about an axis of rotation. The rotor is oriented generally in a horizontal plane and includes an adjustment mechanism for adjusting the angle of the vessel relative to the horizontal plane in response to the centrifugal force generated by orbiting the vessel about the axis of rotation. The dispenser
Another aspect of the present invention is directed to an apparatus for dispensing liquids into a reaction vessel including a rotor, a liquid dispenser, and a controller. The rotor is mounted for rotation about a central axis and carries an array of reaction vessels along a circular path. The liquid dispenser includes a plurality of dispensing nozzles and is positioned above the rotor. The liquid dispenser is arranged for dispensing a liquid from each dispensing nozzle into a respective reaction vessel while the array of reaction vessels moves along the circular path past the liquid dispenser. The controller synchronizes the liquid dispenser and the array of reaction vessels such that the liquid dispenser dispenses liquid into the array of reaction vessels while the rotor is moving.
Another aspect of the present invention is directed to an apparatus for dispensing liquids including a plate and a plurality of dispensing nozzles. The plate includes a first circular array of reaction vessels and a second circular array of reaction vessels. The first and second circular arrays are concentrically arranged about a central axis. The plurality of dispensing nozzles is arranged in a circular pattern above the plate. Each dispensing nozzle is mounted for radial movement about the central axis.
Yet another aspect of the present invention is directed to an apparatus for chemical synthesis utilizing a plate having a plurality of reaction wells therein. The apparatus includes a plate holder, a first reagent dispensing nozzle, an inverting mechanism, and a second solution dispensing nozzle. The plate holder supports the plate in a plurality of positions. The first reagent dispensing nozzle is positioned to dispense a reagent into the plurality of reaction wells for chemical reaction with chemical moieties within the reaction wells when the plate holder supports the plate in an upright position. The inverting mechanism inverts the plate holder and moves the plate between the upright position and an inverted position. The second solution dispensing nozzle is positioned to dispense a solution into the reaction wells when the plate is inverted so that at least a part of the solution can drain by gravity from the reaction wells.
In general, it is an object of the present invention is to provide an apparatus for continuous reagent delivery during solid-phase synthetic reactions.
Another object of the present invention is to provide an apparatus having an improved fluid delivery system and an improved centrifugal rotor assembly.
Another object of the present invention is to provide an apparatus for custom chemical synthesis that is easy to operate, has low initial cost, runs on convenient and easy-to-install consumables, and provides high-throughput combinatorial synthesis of organic molecules.
Yet another object of the present invention is to provide an apparatus for providing continuous liquid addition with respect to motion of the rotor and the fluid delivery system.
The accompanying drawings, which are incorporated in and form a part of this specification, illustrate embodiments of the invention and, together with the description, serve to explain the principles of the invention.